Project Summary Type 1 diabetes has typically been considered a T cell mediated autoimmune diseases. The recently reported, TrialNet-sponsored study using the monoclonal antibody rituximab (anti-CD20) demonstrated that B cells also play a role in the pathogenesis. Specifically, eliminating B cells resulted in significant preservation of beta cell function in patients with recent onset Type 1 diabetes. This proof of concept study now opens the door to optimizing rituximab or other B cell targeted therapies for the treatment and prevention of type 1 diabetes. Although elimination of B cells could potentially lead to increased rates of infections, this concern has not been born out in this study. The overall rate of bacterial and viral infections was no higher in the treated group of subjects compared with placebo treated subjects (less than 3% in either group), and there were no opportunistic infections. However, the small sample size (46 rituximab-treated subjects) limits the ability to generalize this conclusion to rare opportunistic infections. In particular, a concern has been raised about the disease Progressive Multifocal Leukoencephalopathy (PML). PML, caused by the JC polyomavirus (JC virus), is without a cure, and typically leads to death. PML has been reported recently in patients with lymphoma, lupus and rheumatoid arthritis treated with rituximab in combination with other potent immunosuppressive agents. With the complex drug history, it is difficult to ascertain the specific role, if any, of rituximab in this disease. As the subjects in the rituximab/anti-CD20 trial received rituximab without any other immunosuppressive drugs, the JC virus analysis of stored samples from these subjects will allow an unbiased assessment of the risk of JC virus reactivation associated with rituximab. The hypothesis tested in this proposal is that rituximab therapy alone does not reduce the immune control of JC virus allowing JC virus reactivation. While not specifically addressing the mechanism of action of B cells in type 1 diabetes, the data generated from this study will be crucially important in determining the safety of B cell ablation in patients newly diagnosed with type 1 diabetes, particularly since this treatment modality is contemplated for future studies. The hypothesis will be tested by completion of three specific aims Aim 1: Determine and compare the rate of JC virus reactivation in newly diagnosed type 1 diabetes patients over the one a half year period following treatment with rituximab or matching placebo control. Aim 2: Determine the impact of rituximab on preexisting anti-JC virus antibody titers over one and half years. Aim 3: Determine the specificity of JC virus reactivation by comparison to reactivation of other latent viral infections. PUBLIC HEALTH RELEVANCE: The goal of the proposed research is to determine the rate of reactivation of JC virus in patients with type 1 diabetes who participated in a clinical trial with rituximab treatment to preserve insulin secretion. JC virus is the cause of a life threatening central nervous system infection, progressive multifocal leukoencephalopathy, PML. The appearance of this infection in disease states treated with rituximab in combination with other drugs, is slowing the progress in this potential treatment for diabetes. Specifically, we will determine, over time after treatment, the rate of JC virus reactivation and compare it to three other viral infections, CMV, EBV, and BK. We will compare the rates of reactivation between subjects treated with rituximab to a concurrent masked control group to determine if rituximab in general had an impact on reactivation. We will compare anti-viral antibodies levels over time as well.